A hindbrain dopaminergic neural circuit prevents weight gain by reinforcing food satiation

Abstract

The neural circuitry mechanism that underlies dopaminergic (DA) control of innate feeding behavior is largely uncharacterized. Here, we identified a subpopulation of DA neurons situated in the caudal ventral tegmental area (cVTA) directly innervating DRD1-expressing neurons within the lateral parabrachial nucleus (LPBN). This neural circuit potently suppresses food intake via enhanced satiation response. Notably, this cohort of DAcVTA neurons is activated immediately before the cessation of each feeding bout. Acute inhibition of these DA neurons before bout termination substantially suppresses satiety and prolongs the consummatory feeding. Activation of postsynaptic DRD1LPBN neurons inhibits feeding, whereas genetic deletion of Drd1 within the LPBN causes robust increase in food intake and subsequent weight gain. Furthermore, the DRD1LPBN signaling manifests the central mechanism in methylphenidate-induced hypophagia. In conclusion, our study illuminates a hindbrain DAergic circuit that controls feeding through dynamic regulation in satiety response and meal structure.

Molecular and anatomical characterization of parabrachial neurons and their axonal projections

“…The axonal inputs to specific clusters of PBN neurons are being established, either by retrograde rabies virus tracing studies starting with specific Cre-drivers, e.g., Calca Cre ( Liu et al, 2022 ; Rodriguez et al, 2017 ) or by candidate approaches starting with expression of AAV-DIO-ChR2 into distal sites of Cre-driver mouse lines mice and recording photoactivated currents in specific PBN neurons, e.g., input from Cck or Dbh neurons in the NTS to Calca neurons in the PBN ( Roman et al, 2016 ), Oxt neurons in preoptic area to Oxtr neurons in PBN ( Ryan et al, 2017 ), Slc17a6 or Slc32a1 inputs from BNST to Pdyn and Calca neurons in PBN ( Luskin et al, 2021 ). Many other molecularly defined inputs to different subregions of the lateral PBN have been described, e.g., Tac1 , Tacr1, and Gpr83 from spinal cord ( Choi et al, 2020 ), Gfral and Glp1r from area postrema ( Zhang et al, 2021 ), Calcr and Tac1 from NTS ( Cheng et al, 2020 ; Xie et al, 2022 ), Slc17a6 and Dbh from LC ( Yang et al, 2021 ), Slc6a3 from ventral tegmental area ( Han et al, 2021 ), Slc32a1 from substantia nigra reticulata, Npy and Slc32a1 from arcuate nucleus ( Alhadeff et al, 2018 ; Wu et al, 2009 ); Mc4r from the PVN ( Garfield et al, 2015 ), Htr2a, Prkcd, or Sst, Pdyn, and Crh from CEA ( Cai et al, 2014 ; Douglass et al, 2017 ; Raver et al, 2020 ). In the latter cases, knowing the locations and molecular identity of PBN clusters that they innervate would refine connectivity maps and provide insight into potential functions.…”

D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum

“…5A ). The 20 Hz optical stimulation same as used to activate VTA D1 neurons was utilized [ 56 – 59 ]. Activating DA neurons and GABA neurons oppositely changed mouse locomotor activity, but activating glutamate neurons had no effect (Fig.…”

Molecular and Anatomical Characterization of Parabrachial Neurons and Their Axonal Projections

“…Many other molecularly defined inputs to different subregions of the lateral PBN have been described, e.g., Tacr1 and Gpr83 from spinal cord (Choi et al, 2020), Gfral, Glp1r from area postrema (Zhang et al, 2021), Calcr from NTS (Cheng et al, 2020), Slc17a6/Dbh from LC (Yang et al, 2021), Slc6a3 from ventral tegmental area (Han et al, 2021), Slc32a1 from substantia nigra reticulata, Npy/Slc32a1 from arcuate nucleus (Alhadeff et al, 2018, Wu et al, 2009; Mc4r from the PVN (Garfield et al, 2015), Htr2a, Prkcd, or Sst/Pdyn/Crh from CEA (Cai et al, 2014, Douglass et al, 2017, Raver et al, 2020. In each of these cases, knowing the locations and identity of PBN clusters that they innervate would refine connectivity maps and provide greater insight into potential functions.…”

“…The axonal inputs to specific clusters of PBN neurons are beginning to be established, either by retrograde rabies virus tracing studies starting with specific Cre-drivers, e.g., Calca Cre (Liu et al, 2022, Rodriguez et al, 2017) or by candidate approaches starting with expression AAV-DIO-ChR2 into distal sites of Cre-driver lines of mice and recording photoactivated currents in specific PBN neurons, e.g., input from Cck or Dbh neurons in the NTS to Calca neurons in the PBN (Roman et al, 2016), Oxt neurons in pre-optic area to Oxtr neurons in PBN (Ryan et al, 2017), Slc17a6 or Slc32a1 inputs from BNST to Pdyn and Calca neurons in PBN (Luskin et al, 2021). Many other molecularly defined inputs to different subregions of the lateral PBN have been described, e.g., Tacr1 and Gpr83 from spinal cord (Choi et al, 2020), Gfral, Glp1r from area postrema (Zhang et al, 2021), Calcr from NTS (Cheng et al, 2020), Slc17a6/Dbh from LC (Yang et al, 2021), Slc6a3 from ventral tegmental area (Han et al, 2021), Slc32a1 from substantia nigra reticulata, Npy/Slc32a1 from arcuate nucleus (Alhadeff et al, 2018, Wu et al, 2009); Mc4r from the PVN (Garfield et al, 2015), Htr2a, Prkcd, or Sst/Pdyn/Crh from CEA (Cai et al, 2014, Douglass et al, 2017, Raver et al, 2020). In each of these cases, knowing the locations and identity of PBN clusters that they innervate would refine connectivity maps and provide greater insight into potential functions.…”